This invention relates to the fields of pharmaceutical and organic chemistry and provides novel benzofuran compounds which are useful for the treatment of the various medical indications associated with post-menopausal syndrome, and uterine fibroid disease, endometriosis, and aortal smooth muscle cell proliferation. The present invention further relates to intermediate compounds useful for preparing the pharmaceutically active compounds of the present invention, and pharmaceutical compositions. Furthermore, the present invention relates to a novel process for preparing the pharmaceutically active compounds of the present invention.
xe2x80x9cPost-menopausal syndromexe2x80x9d is a term used to describe various pathological conditions which frequently affect women who have entered into or completed the physiological metamorphosis known as menopause. Although numerous pathologies are contemplated by the use of this term, three major effects of post-menopausal syndrome are the source of the greatest long-term medical concern: osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancer, particularly breast and uterine cancer.
Osteoporosis describes a group of diseases which arise from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.
There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post-menopausal osteoporosis.
The most vulnerable tissue in the bone to the effects of post-menopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which inter-connect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This inter-connected network of trabeculae gives lateral support to the outer cortical structure and is critical to the bio-mechanical strength of the overall structure. In post-menopausal osteoporosis, it is, primarily, the net resorption and loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in post-menopausal women, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, e.g., the vertebrae, the neck of the weight bearing bones such as the femur and the fore-arm. Indeed, hip fracture, colles fractures, and vertebral crush fractures are hall-marks of post-menopausal osteoporosis.
At this time, the only generally accepted method for treatment of post-menopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low primarily because estrogen treatment frequently produces undesirable side effects.
Throughout premenopausal time, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that post-menopausal women having estrogen replacement therapy have a return of serum lipid levels to concentrations to those of the pre-menopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side-effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which would regulate the serum lipid level as does estrogen, but would be devoid of the side-effects and risks associated with estrogen therapy.
The third major pathology associated with post-menopausal syndrome is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such neoplasms are not solely limited to a post-menopausal women, they are more prevalent in the older, post-menopausal population. Current chemotherapy of these cancers have relied heavily on the use of anti-estrogen compounds such as, for example, Tamoxifen. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side-effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may, therefore, be contraproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an anti-estrogen compound having negligible or no estrogen agonist properties on reproductive tissues.
In response to the clear need for new pharmaceutical agents which are capable of alleviating the symptoms of, inter alia, post-menopausal syndrome, the present invention provides new benzofuran compounds, pharmaceutical compositions thereof, and methods of using such compounds for the treatment of post-menopausal syndrome and other estrogen-related pathological conditions such as those mentioned below.
Uterine fibrosis (uterine fibroid disease) is an old and ever present clinical problem which goes under a variety of names, including uterine hypertrophy, uterine lieomyomata, myometrial hypertrophy, fibrosis uteri, and fibrotic metritis. Essentially, uterine fibrosis is a condition where there is an inappropriate deposition of fibroid tissue on the wall of the uterus.
This condition is a cause of dysmenorrhea and infertility in women. The exact cause of this condition is poorly understood but evidence suggests that it is an inappropriate response of fibroid tissue to estrogen. Such a condition has been produced in rabbits by daily administrations of estrogen for 3 months. In guinea pigs, the condition has been produced by daily administration of estrogen for four months. Further, in rats, estrogen causes similar hypertrophy.
The most common treatment of uterine fibrosis involves surgical procedures both costly and sometimes a source of complications such as the formation of abdominal adhesions and infections. In some patients, initial surgery is only a temporary treatment and the fibroids regrow. In those cases a hysterectomy is performed which effectively ends the fibroids but also the reproductive life of the patient. Also, gonadotropin releasing hormone antagonists may be administered, yet their use is tempered by the fact they can lead to osteoporosis. Thus, there exists a need for new methods for treating uterine fibrosis, and the methods of the present invention satisfy that need.
Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrial masses or peritoneal cavity and often leads to infertility. The cause of the symptoms of this condition appear to be ectopic endometrial growths which respond inappropriately to normal hormonal control and are located in inappropriate tissues. Because of the inappropriate locations for endometrial growth, the tissue seems to initiate local inflammatory-like responses causing macrophage infiltration and a cascade of events leading to initiation of the painful response. The exact etiology of this disease is not well understood and its treatment by hormonal therapy is diverse, poorly defined, and marked by numerous unwanted and perhaps dangerous side effects.
One of the treatments for this disease is the use of low dose estrogen to suppress endometrial growth through a negative feedback effect on central gonadotropin release and subsequent ovarian production of estrogen; however, it is sometimes necessary to use continuous estrogen to control the symptoms. This use of estrogen can often lead to undesirable side effects and even the risk of endometrial cancer.
Another treatment consists of continuous administration of progestins which induces amenorrhea and by suppressing ovarian estrogen production can cause regressions of the endometrial growths. The use of chronic progestin therapy is often accompanied by the unpleasant CNS side effects of progestins and often leads to infertility due to suppression of ovarian function.
A third treatment consists of the administration of weak androgens, which are effective in controlling the endometriosis; however, they induce severe masculinizing effects. Several of these treatments for endometriosis have also been implicated in causing a mild degree of bone loss with continued therapy. Therefore, new methods of treating endometriosis are desirable.
Smooth aortal muscle cell proliferation plays an important role in diseases such as atherosclerosis and restenosis. Vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) has been shown to be a tissue response characterized by an early and late phase. The early phase occurring hours to days after PTCA is due to thrombosis with some vasospasms while the late phase appears to be dominated by excessive proliferation and migration of aortal smooth muscle cells. In this disease, the increased cell motility and colonization by such muscle cells and macrophages contribute significantly to the pathogenesis of the disease. The excessive proliferation and migration of vascular aortal smooth muscle cells may be the primary mechanism to the reocclusion of coronary arteries following PTCA, atherectomy, laser angioplasty and arterial bypass graft surgery. See xe2x80x9cIntimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplasty,xe2x80x9d Austin et al., Journal of the American College of Cardiology, 8: 369-375 (August 1985).
Vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by percutaneous transluminal coronary angioplasty (PTCA), atherectomy, laser angioplasty and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, reocclusion occurs within three to six months after the procedure. The current strategies for treating vascular restenosis include mechanical intervention by devices such as stents or pharmacologic therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonist, steroids, and prostacyclin. These strategies have failed to curb the reocclusion rate and have been ineffective for the treatment and prevention of vascular restenosis. See xe2x80x9cPrevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a xe2x80x98Magic Bulletxe2x80x99,xe2x80x9d Hermans et al., American Heart Journal, 122: 171-187 (July 1991).
In the pathogenesis of restenosis excessive cell proliferation and migration occurs as a result of growth factors produced by cellular constituents in the blood and the damaged arterial vessel wall which mediate the proliferation of smooth muscle cells in vascular restenosis.
Agents that inhibit the proliferation and/or migration of smooth aortal muscle cells are useful in the treatment and prevention of restenosis. The present invention provides for the use of compounds as smooth aortal muscle cell proliferation inhibitors and, thus inhibitors of restenosis.
The present invention relates to compounds of formula I 
wherein
R is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar in which Ar is optionally substituted phenyl, or xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl);
R1 is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar in which Ar is optionally substituted phenyl, xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), chloro or bromo;
n is 2 or 3; and
R2 and R3 each are independently C1-C4 alkyl, or combine to form 1-piperidinyl, 1-pyrrolidinyl, methyl-1-piperidinyl, dimethyl-1-piperidinyl, 4-morpholino, or 1-hexamethyleneimino;
or a pharmaceutically acceptable salt thereof.
Also provided are compounds of formula IX which are useful for preparing compounds of formula I.
The present invention also relates to pharmaceutical compositions containing compounds of formula I, optionally containing estrogen or progestin, and the use of such compounds, alone, or in combination with estrogen or progestin, for alleviating the symptoms of post-menopausal symptoms, particularly osteoporosis, cardiovascular related pathological conditions, and estrogen-dependent cancer. As used herein, the term xe2x80x9cprogestinxe2x80x9d includes compounds having progestational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, and the like.
The present invention further relates to the use of the compounds of the present invention for inhibiting uterine fibroid disease and endometriosis in women and aortal smooth muscle cell proliferation, particularly restenosis, in humans.
Furthermore, the present invention relates to a process for preparing a compound of formula Ia 
wherein
Ra and R1a each are xe2x80x94OH or xe2x80x94O(C1-C4 alkyl);
R2 and R3 each are independently C1-C4 alkyl, or combine to form C4-C6 polymethylene, xe2x80x94CH2CH(CH3)CH2CH2xe2x80x94, xe2x80x94CH2C(CH3)2CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94; and
n is 2 or 3; or a pharmaceutically acceptable salt thereof, which comprises
a) optionally dealkylating a compound of formula II 
wherein Ra, R1a, R2, R3, and n are as defined above;
b) reacting said formula II compound with a reducing agent in the presence of a solvent having a boiling point in the range from about 150xc2x0 C. to about 200xc2x0 C., and heating the mixture to reflux; and
c) optionally salifying the reaction product form step b).
One aspect of the present invention includes compounds of formula I 
wherein
R is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar in which Ar is optionally substituted phenyl, or xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl);
R1 is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar in which Ar is optionally substituted phenyl, xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), chloro or bromo;
n is 2 or 3; and
R2 and R3 each are independently C1-C4 alkyl, or combine to form 1-piperidinyl, 1-pyrrolidinyl, methyl-1-piperidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, or 1-hexamethyleneimino;
or a pharmaceutically acceptable salt thereof.
General terms used in the description of compounds herein described bear their usual meanings. For example, xe2x80x9cC1-C4 alkylxe2x80x9d refers to straight or branched aliphatic chains of 1 to 4 carbon atoms including methyl, ethyl, propyl, isopropyl, butyl, n-butyl, and the like; and xe2x80x9cC1-C6 alkylxe2x80x9d encompasses the groups included in the definition of xe2x80x9cC1-C4 alkylxe2x80x9d in addition to groups such as pentyl, isopentyl, hexyl, isohexyl, and the like.
The term xe2x80x9csubstituted phenylxe2x80x9d refers to a phenyl group having one or more substituents selected from the group consisting of C1-C4 alkyl, C1-C5 alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl. xe2x80x9cC1-C5 alkoxyxe2x80x9d represents a C1-C5 alkyl group attached through an oxygen bridge such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
The compounds of the present invention are derivatives of benzo [b] furan which is named and numbered according to the Ring Index, The American Chemical Society, as follows 
The starting materials of the present invention, compounds of formula II below, are made essentially as described in U.S. Pat. Nos. 4,133,814, issued Jan. 9, 1979, 4,418,068, issued Nov. 29, 1983, and 4,380,635, issued Apr. 19, 1983, each of which is herein incorporated by reference. This process provides a convenient process which acylates a methylated starting compound and then optionally dealkylates it to obtain the desired dihydroxy product. The acylation and dealkylation may be performed in successive steps in a single reaction mixture or the intermediate may be isolated and the dealkylation step be performed in a separate reaction. 
wherein Ra, R1a, R2, R3, and n are as defined above, or a salt thereof.
In the preparation of a formula II compound, an alkyl-protected compound of formula III 
is most easily obtained by reacting a 3-(C1-C4 alkyl)phenol, preferably 3-methoxyphenol, and a-bromo-4-(C1-C4 alkyl)acetophenone, preferably 4-methoxyacetophenone, in the presence of a strong base at a relatively low temperature, to form a-(3-methoxyphenoxy)-4-methoxyacetophenone, which is then ring closed with an agent such as polyphosphoric acid at a high temperature to obtain the intermediate compound of formula III.
The acylation of this invention is a Friedel-Crafts acylation, and is carried out in the usual way, using a Lewis acid such as aluminum chloride or bromide, preferably the chloride, as the acylation catalyst.
The acylation is ordinarily carried out in a solvent, and any inert organic solvent which is not significantly attacked by the conditions may be used. For example, halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform, and the like may be used, as can aromatics such as benzene, chlorobenzene, and the like. It is preferred to use a halogenated solvent, especially dichloromethane.
It has been found that toluene is rather easily acylated under the conditions used in the Friedel-Crafts acylation. Therefore, it is important, when toluene is used in an earlier step of the process, to remove it as completely as possible from the protected starting compound. Furthermore, if toluene remains following preparation of a compound of formula IV below, it should be removed to avoid wasting the acylating agent and contaminating the product.
The acylations may be carried out at temperatures from about xe2x88x9230xc2x0 C. to about 100xc2x0 C., preferably at about ambient temperature, in the range of from about 15xc2x0 C. to about 30xc2x0 C.
The acylating agent is an active form of the appropriate benzoic acid of formula IV 
wherein Ra is chloro or bromo, and R2 and R3 are as defined above. The preferred acylating agents are those wherein Ra is chloro. Thus, using this reaction scheme, the most highly preferred individual acylating agents are 4-[2-(piperidin-1-yl)ethoxy]benzoyl chloride, 4-[2-(hexamethyleneimin-1-yl)ethoxy]benzoyl chloride, and 4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl chloride.
The acyl chloride used as an acylating agent may be prepared from the corresponding carboxylic acid by reaction with a typical chlorinating agent such as thionyl chloride. Care must be taken to remove any excess chlorinating agent from the acyl chloride. Most conveniently, the acyl chloride is formed in situ, and the excess chlorinating agent is removed under vacuum.
It is generally preferred that an equimolar amount of the compounds of formulae III and IV are reacted together. If desired, a small excess of either reactant may be added to assure the other is fully consumed. It is generally preferred to use a large excess of the acylation catalyst, such as about 2-12 moles per mole of product, preferably about 5-10 moles of catalyst per mole of product.
The acylation is rapid. Economically brief reaction times, such as from about 15 minutes to a few hours provide high yields of the acylated intermediate. Longer reaction times may be used if desired, but are not usually advantageous. As usual, the use of lower reaction temperatures call for relatively longer reaction times.
The acylation step is ended and the optional dealkylation step is begun by the addition of a sulfur compound selected from the group consisting of methionine and compounds of the formula
Xxe2x80x94Sxe2x80x94Y
wherein X is hydrogen or unbranched C1-C4 alkyl, and Y is C1-C4 alkyl or phenyl. The sulfur compounds are, preferably, the alkylthiols, such as methanethiol, ethanethiol, isopropanethiol, butanethiol, and the like; dialkyl sulfides, such as diethyl sulfide, ethyl propyl sulfide, butyl isopropyl sulfide, dimethyl sulfide, methyl ethyl sulfide, and the like; benzenethiol; methionine; and alkyl phenyl sulfides, such as methyl phenyl sulfide, ethyl phenyl sulfide, butyl phenyl sulfide, and the like.
It has been found that dealkylation is most efficient when a substantial excess of the sulfur compound is used, in the range of about 4 to about 10 moles per mole of the starting benzofuran. The process may be carried out, although less efficiently, with a smaller amount of the sulfur compound (in the range of about 2 to 3 moles per mole of the starting compound). It is also possible to use a small amount of the sulfur compound, and to improve the yield by the addition of about 1 to 3 moles of an alkali metal halide, such as sodium, potassium, or lithium chloride, bromide, or iodide.
The dealkylation reaction goes well at about ambient temperature, in the range of from about 15xc2x0 C. to about 30xc2x0 C., and such operation is preferred. The dealkylation may be carried out, however, at temperatures in the range of from about xe2x88x9230xc2x0 C. to about 50xc2x0 C. if it is desired to do so. Short reaction times, in the range of about one hour, have been found to be sufficient.
After the product has been dealkylated, it is recovered and isolated by conventional means. It is customary to add water to decompose the complex of the acylation catalyst. Addition of dilute aqueous acid is often advantageous. The product precipitates in many instances, or may be extracted with an organic solvent according to conventional methods. The examples below further illustrate the isolation.
In an alternative, preferred process, an intermediate compound of formula V 
wherein Ra and R1 are as defined above, is prepared by the reaction of 2-hydroxy-4-methoxybenzaldehyde and 1-(4-(C1-C4 alkoxy)phenyl)-2-(4-(C1-C4 alkoxy)phenyl)ethanone, essentially as described in Preparation 3, infra. This reaction usually employs equimolar amounts of the two reactants although other ratios are operable. The reaction is performed in a non-reactive solvent such as ethyl acetate, chloroform, and the like, in the presence of an acid. Hydrochloric acid, particularly in the form of anhydrous hydrogen chloride, is an especially preferred acid. Lower alkyl alcohols are usually added to the non-polar solvent so as to retain more of the hydrochloric acid created in situ, with ethanol and methanol being especially preferred. The reaction is performed at temperatures ranging from ambient temperature up to the reflux temperature of the mixture. This reaction results in the preparation of the compound of formula VI 
(or an equivalent anion if hydrochloric acid is not used), which is then oxidized to the compound of formula V by the action of hydrogen peroxide. The intermediate of formula VI may be isolated or may preferably be converted to the compound of Formula V in the same reaction vessel.
The compound of formula V is then selectively dealkylated, essentially as described in Preparation 4, infra, to yield the compound of formula VII 
wherein Ra and R1a are as defined above. The ether form of compounds of formula II is then produced by the substitution of the hydrogen on the hydroxy group by an alkyl group.
The last step in preparing starting materials of formula II via the present process involves alkylating the selectively dealkylated compound of formula VII with an appropriate alkylation agent of formula VIII below, essentially as described in Preparation 5B, infra. 
wherein Z is a leaving group such as chloro or bromo, and n, R2, and R3 are as defined above.
This reaction usually employs equimolar to a slight excess of a formula VIII compound relative to the formula VII substrate. The reaction is performed in a non-reactive solvent such as N,N-dimethylformamide and the like, in the presence of a base such as, for example, potassium carbonate. The reaction is performed at temperatures from about 80xc2x0 C. to about 120xc2x0 C. and allowed to run until compounds of formula II are prepared. The reaction typically takes about 1 hour when run at 100xc2x0 C. However, the progress of the reaction may be monitored by using standard chromatographic techniques.
Preferred formula II starting materials are those in which n is 2, and R2 and R3 are methyl or ethyl, or R2 and R3 are combined to form a pyrrolidino moiety or a piperidino moiety. Of these, combining R2 and R3 to form a piperidino moiety is especially preferred.
Compounds of formula IX generally are prepared by adding a formula II compound, or, preferably, the hydrochloride salt thereof, to an appropriate solvent, and reacting the resulting mixture with a reducing agent such as, for example, lithium aluminum hydride (LAH), under an inert gas such as nitrogen. The amount of reducing agent used in this reaction is an amount sufficient to reduce the carbonyl group of a formula II compound to form a carbinol of formula IX below. Generally, a liberal excess of the reducing agent per equivalent of the substrate is used. 
wherein Ra, R1a, R2, R3, and n of formula IX are as defined above, or a salt thereof.
Appropriate solvents include any solvent or mixture of solvents which will remain inert under reducing conditions. Suitable solvents include ether, dioxane, and tetrahydrofuran (THF).
The temperature employed in this step is that which is sufficient to effect completion of the reduction reaction. Ambient temperature, in the range from about 17xc2x0 C. to about 25xc2x0 C., generally is adequate.
The length of time for this step is that amount necessary for the reaction to occur. Typically, this reaction takes from about 1 to about 20 hours. The optimal time can be determined by monitoring the progress of the reaction via conventional chromatographic techniques.
Optionally, the C1-C4 alkoxy moieties of a formula IX compound may be dealkylated, via standard procedures, prior to further reduction as described below. The resulting diphenolic compounds of formula IXa are considered to be part of the present invention 
wherein R2, R3, and n are as defined above.
The carbinol products from this reaction are extracted essentially via the method described in Example 1, infra, are novel, and are useful intermediates for the preparation of formula I compounds of the present invention by further reduction.
In formula IX, the carbon atom designated xe2x80x9c*xe2x80x9d is an asymmetric center. Thus, these compounds can have an Rxe2x80x94 or Sxe2x80x94configuration, or a mixture thereof. Both enantiomers are considered to be part of the present invention.
Once a carbinol of the present invention is prepared, one option is to further reduce such a carbinol via standard procedures, to give a compound of formula I.
Typically a carbinol of formula IX is suspended in an appropriate solvent and cooled under an inert gas such as nitrogen. To this suspension is added a suitable trialkyl silane reducing agent, preferably triethyl silane, and a reasonably strong protic acid such as hydrochloric acid, trifluoracetic acid, and the like.
Appropriate solvents can be any solvent or mixture of solvents which remain inert under the reaction conditions employed in the process. For example, halogenated alkane solvents such as dichloromethane and 1,2-dichloroethane, as well as haloaromatics such as chlorobenzene and the like may be used. Of these, dichloromethane is preferred.
The temperature employed in this step is that which is sufficient to effect completion of the present reduction process. Typically, the reaction is cooled to about 0xc2x0 C. and the reaction solution is kept on ice until the reaction is complete; however, ambient temperature also is satisfactory. In general, this reaction is completed in less than three hours, and the progress of the reaction can be monitored via standard techniques.
In particular cases, when phenolic hydroxys are present in the compounds of formula IXa, the use of triethylsilyl as a reducing agent can lead to the formation of the silyl adduct of the phenol. On occasion, this adduct can be isolated as seen in Example 2. In other cases, traces of such silylated phenols can be seen as minor impurities. The intermediate methylene free bases which contain such impurities are cleaved to the free phenol when the compounds are converted to their hydrochloride salts, as seen in Example 3, intra.
Alternatively, a novel process may be used to prepare compounds of formula Ia of the present invention by reducing a ketone of formula II above. This process is shown below in Scheme I. 
wherein
Ra, R1a, R2, R3, and n are as defined above, or a pharmaceutically acceptable salt thereof.
In this process, a formula II compound, or a salt thereof, is optionally dealkylated and then reacted with a reducing agent such as lithium aluminum hydride in the presence of a solvent having a boiling point in the range from about 150xc2x0 C. to about 200xc2x0 C. The reaction product of this reduction step can then optionally be salified via standard procedures. Alternatively, the reduction step of the present process may first be carried out, followed by the optional dealkylation step. Preferably, each step of this novel process is carried out in separate vessels, but it is possible to carry out each step of the present process in the same vessel.
The amount of reducing agent used in this reaction is an amount sufficient to reduce the carbonyl group of a formula II compound to form a compound of formula I. Generally, a generous excess of the reducing agent per equivalent of the substrate is used.
The solvent used in the present process is required to have a relatively high boiling point, in the range from about 150xc2x0 C. to about 200xc2x0 C., as represented by solvents such as, for example n-propylbenzene, diglyme (1,1xe2x80x2-oxybis[2-methoxyethane]), and anisole, and Red-Al(copyright) {[sodium bis(2-methoxyethoxylaluminum hydride)]} which also is used as the reducing agent. Of these, n-propylbenzene is the preferred solvent with formula II compounds as shown above. The alkoxy substituents of compounds of formula II may first be dealkylated, to form a diphenol compound via standard procedures herein described, which can then be reduced via the present, novel process to provide formula I compounds. In this instance, Red-Al is the preferred reducing agent.
The temperature used in this reaction is that which is sufficient to complete the reduction reaction. Preferably, the reaction mixture is heated to reflux for about 15 minutes to about 6 hours, and allowed to cool to ambient temperature. A small amount of deionized water is added to the mixture followed by the addition of a small aliquot of 15% sodium hydroxide: deionized water (w/w). The mixture is stirred until the reaction is complete. The optimal amount of time for this reaction to run, typically from about 10 minutes to about 1 hour, can be determined by monitoring the progress of the reaction via standard techniques.
The formula I products from this reduction reaction are extracted essentially as described in Example 7, infra.
Formula I compounds in which R and R1 are xe2x80x94OH and/or xe2x80x94O(C1-C4 alkyl) are novel and can be used as pharmaceutically active agents for the methods herein described, or can be derivalitized to provide other novel compounds of formula I which also are useful for the present methods.
For example, when R and/or R1 are xe2x80x94O(C1-C4 alkyl), (thus, not having been dealkylated as one above option provides), such groups can be removed via standard dealkylation techniques to prepare an especially preferred compound of formula I.
Other formula I compounds are prepared by replacing the newly formed R and R1 hydroxy groups with a moiety of the formula xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar in which Ar is optionally substituted phenyl, or xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alky) via well known procedures. See, e.g., U.S. Pat. No. 4,358,593, supra.
For example, when a xe2x80x94Oxe2x80x94CO(C1-C6 alkyl) or xe2x80x94Oxe2x80x94COxe2x80x94Ar group is desired, the dihydroxy compound of formula I is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed with anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine, and the like. The reaction also may be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, and the like, to which at least one equivalent of an acid scavenger, such as a tertiary amine, has been added. If desired, acylation catalysts such as 4-dimethylaminepyridine or 4-pyrrolidinopyridine may be used. See, e.g., Haslam, et al., Tetrahedron, 3:2409-2433 (1980).
The acylation reactions which provide the aforementioned R and R1 groups are carried out at moderate temperatures in the range from about xe2x88x9225xc2x0 C. to about 100xc2x0 C., frequently under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually adequate for the reaction to run.
Such acylations of the hydroxy group also may be performed by acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents or heat. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid, and the like are used.
The aforementioned R and R1 groups also may be provided by forming an active ester of the appropriate acid, such as the esters formed by such known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan, 38:1979 (1965), and Chem. Ber., 788 and 2024 (1970).
Each of the above techniques which provide xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl) and xe2x80x94Oxe2x80x94COxe2x80x94Ar groups are carried out in solvents as discussed above. These techniques which do not produce an acid product in the course of the reaction, of course, do not call for the use of an acid scavenger in the reaction mixture.
When a formula I compound is desired in which R and R1 is xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), the formula I dihydroxy compound is reacted with, for example, a derivative of the appropriate sulfonic acid such as a sulfonyl chloride, bromide, or sulfonyl ammonium salt, as taught by King and Monoir, J. Am. Chem. Soc., 97:2566-2567 (1975). The dihydroxy compound also can be reacted with the appropriate sulfonic anhydride. Such reactions are carried out under conditions such as were explained above in the discussion of reaction with acid halides and the like.
Compounds of formula I can be prepared so that R and R1 bear different biological protecting groups or, preferably, are prepared so that R and R1 each bear the same biological protecting group. Preferred protecting groups include xe2x80x94OCH3, xe2x80x94Oxe2x80x94COxe2x80x94C(CH3)3, xe2x80x94Oxe2x80x94COxe2x80x94C6H5, and xe2x80x94Oxe2x80x94SO2xe2x80x94(CH2)3xe2x80x94CH3.
The term xe2x80x9cbiological protecting groupsxe2x80x9d refers to those R and R1 substituents which delay, resist, or prohibit removal of such groups in a biological system such as, for example, following administration of a formula I compound containing the above-described R and R1 groups to a human. Such compounds of formula I also are useful for the methods herein described.
Although the free-base form of formula I compounds can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form. Thus, the compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids, and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, xcex2-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.
The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
Likewise, salts of formula IX also can be prepared by the procedures discussed above.
The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.